The major goal of this application is to discover and develop medications for the treatment of substance abuse. The compounds developed will also serve as biochemical probes useful in gaining a better understanding of the biochemical and molecular mechanisms of cocaine and amphetamine addiction and withdrawal. Clinical evidence indicates that the anorectic therapy PHEN/FEN, a combination of releasers phentermine (DA releaser) and fenfluramine (5-HT releaser) decreases cocaine dependence; the primary objective of this application is to discover and develop novel classes of dual releasers which mimic the combination therapy. The scope of this study will include: (1) the synthesis of several small molecule libraries based on known releasers concurrent with the synthesis other potential small phenylamine scaffolds; (2) in vitro evaluation of the compounds using a high throughput releaser assay; (3) the development of a theoretical model for selective releaser activity; and (4) in vivo evaluation in animal models. The "dopamine hypothesis" of cocaine reward which drives much of current addiction research has failed to find DAergic medications. Some recent evidence suggests that the reward mechanism may involve 5-HT in a much larger way than previously thought. A "dual deficit" model for cocaine reward is thus the basis for the project. Compounds that demonstrate DA and 5-HT releasing activity, but not NE, will be tested for NE uptake. Candidates will also be evaluated for 5-HT2A, MAO-A, and MAO-B in vitro activity. Compounds which fit our in vitro criteria will be tested in vivo for neurotoxicity and their releasing properties confirmed via in vivo microdialysis. We will also submit interesting candidates to the NIDA Cocaine Treatment Discovery Program for further in vitro and in vivo evaluation.